The present invention relates to ophthalmic histamine-containing preparations for the treatment of ocular irritation. More precisely, the invention relates to an aqueous formulation of histamine or similar compounds, to be instilled in and around the eye as well as in the conjunctival sac to treat various forms of ocular irritation.
There are a number of patents that address various ophthalmic formulations to ease ocular irritation. For example, U.S. Pat. Nos. 5,895,645; 5,877,154; 5,872,086; and 5,861,148; each recite an ophthalmic solution formulated to ease ocular irritation. However, none of these patents discuss the use of histamine-containing formulations for the reduction of ocular irritation.
One embodiment of the present invention is an ophthalmic composition for use in reducing ocular irritation, comprising a compound selected from the group consisting of histamine, a histamine receptor analog, serotonin and a serotonin analog, and a pharmaceutically acceptable ophthalmic carrier. In one aspect of this embodiment, the histamine is histamine dihydrochloride or histamine phosphate. Preferably, the histamine is present at a concentration of between about 0.001% and 10% by weight. More preferably, the histamine is present at a concentration of between about 0.05% and 5% by weight. Most preferably, the histamine is present at a concentration of between about 0.1% and 1% by weight. In one aspect of this preferred embodiment, the pharmaceutically acceptable carrier is an aqueous solution, gel or ointment. Preferably, the aqueous solution has a pH of between about 6.8 and 7.6.
Another embodiment of the present invention provides a method for treating ocular irritation in a subject in need thereof, comprising administering to the subject an effective ocular irritation-reducing amount of an ophthalmic composition comprising a compound selected from the group consisting of histamine, a histamine receptor analog, serotonin and a serotonin analog, and a pharmaceutically acceptable ophthalmic carrier. In one aspect of this embodiment, the histamine is histamine dihydrochloride or histamine phosphate. Advantageously, the subject is a human. In one aspect of this embodiment, the ocular irritation is caused by exposure to a pollutant, chemical compound, dust particles, ultraviolet light or a pathogen. The pathogen can be, for example, a virus or bacterium. In one aspect of this embodiment, the virus is a herpes virus. In another aspect of this embodiment, the bacterium is Neisseria gonorrhea. The ocular irritation can be caused by, for example, laser in situ keratomileusis (LASIK), radial keratotomy (RK), photo refractive keratectomy (PRK) or cataract surgery, or an allergic reaction. The compositions described herein can be administered by spraying into the eye, application of an ophthalmic gel or eye drops. Preferably, 1-2 drops of the composition is administered per eye, between 4 and 8 times per day.
Another embodiment of the present invention is a composition comprising a compound selected from the group consisting of histamine, a histamine receptor analog, serotonin and a serotonin analog, and a pharmaceutically acceptable ophthalmic carrier for use in reducing ocular irritation in a subject. In one aspect of this embodiment, the histamine is histamine dihydrochloride or histamine phosphate. The ophthalmic carrier is preferably an aqueous solution, gel or ointment. Preferably, the histamine is present at a concentration of between about 0.001% and 10% by weight. More preferably, the histamine is present at a concentration of between about 0.05% and 5% by weight. Most preferably, the histamine is present at a concentration of between about 0.1% and 1% by weight.
Another embodiment of the present invention provides the use of a composition comprising a compound selected from the group consisting of histamine, a histamine receptor analog, serotonin and a serotonin analog, and a pharmaceutically acceptable ophthalmic carrier for reducing ocular irritation in a subject. In one aspect of this embodiment, the histamine is histamine dihydrochloride or histamine phosphate. Preferably, the histamine is present at a concentration of between about 0.001% and 10% by weight. More preferably, the histamine is present at a concentration of between about 0.05% and 5% by weight. Most preferably, the histamine is present at a concentration of between about 0.1% and 1% by weight.
The present invention relates to the use of ophthalmic pharmaceutical formulations comprising histamine for reducing ocular irritation. Ocular irritation can result from various ophthalmic surgical procedures, contact lens wear, exposure to allergens, ocularly irritating chemical compounds, pollutants, dust particles, ultraviolet light, and various pathogenic agents that cause conjunctivitis, including various infections of the eye such as herpetic infections, other viral infections, and bacterial infections. Surprisingly, ophthalmic administration of histamine-containing formulations is effective to reduce ocular irritation.
The histamine-containing formulations described herein preferably comprise histamine dihydrochloride, however, other forms of histamine, such as histamine phosphate, as well as histamine receptor analogs, serotonin and serotonin analogs are also contemplated for use in the present invention.
The histamine is present in the pharmaceutical formulations in an amount effective to reduce ocular irritation. The concentration of histamine, or a similarly functioning compound, in the formulations described herein is expressed in terms of percent histamine by weight of the total composition. For example, in one embodiment, histamine is present in an amount between about 0.001 and 10 percent by weight. In another embodiment, histamine is present in an amount between about 0.05 and 5 percent by weight. In still another embodiment, histamine is present in an amount of between about 0.1 and 1 percent by weight.
The formulations described herein comprise histamine and a pharmaceutically acceptable carrier. In a preferred embodiment, the carrier is a sterile, aqueous solution that is buffered with compounds such as phosphate buffers, carbonate buffers and the like. The composition is preferably provided as a buffered aqueous solution having a viscosity of from about 1 to 50 centipoise (cps). In another preferred embodiment, the composition is formulated as a viscous liquid having a viscosity of between about 50 and several thousand cps using viscosity-enhancing agents such as, for example propylene glycol, hydroxymethyl cellulose or glycerin.
Other ophthalmic histamine-containing pharmaceutical carriers are also contemplated, including, for example, gels and ointments. The formulations can also comprise ingredients which regulate the osmolarity of the final formulation, as well as the pH of the formulations.
For example, the resulting preparations for ocular use are advantageously hypotonic, and have an osmolarity of between about 140 and 280 mOsm/l, and a pH of between about 6.8 and 7.6. The osmolarity of the solutions can be adjusted by means of well known osmolarity adjusting agents such as sodium chloride, potassium chloride and monosaccharides. Alternatively, the resulting preparations can be isotonic, or in another embodiment, the resulting preparations can be hypertonic. The present formulations may also contain other conventional ingredients used in ophthalmic preparations, such as dextrose, preservatives (e.g. Thimerosal(trademark), i.e., sodium ethylmercurithiosalicylate (Sigma; St. Louis, Mo.), benzalkonium chloride), corticosteroids (e.g. prednisone), analgesics (e.g., ibuprofen), antibiotics (e.g., gentamicin, streptomycin), antioxidants (e.g. ascorbic acid, BHA, BHT), demulcents (e.g., glycerin, propylene glycol), and the like. Descriptions of compounds used in standard ophthalmic formulations may be found in, for example, Remington""s Pharmaceutical Sciences, latest edition, Mack Publishing Co. Easton, Pa., and in U.S. Pat. Nos. 5,951,971, 5,861,148, and 5,800,807.
The pH of the formulations described herein can be adjusted to the desired value by adding an acid, such as hydrochloric acid, or a base such as sodium hydroxide, until the pH of the formulation falls within the range described above. Such adjustments are preferably made without increasing the ionic strength of the formulation to beyond acceptable levels.
The present histamine-containing compositions are prepared according to conventional techniques by mixing the relative ingredients in appropriate amounts in sterile water, or preparing histamine-containing gels and ointments using gel and ointment preparation techniques well known in the pharmaceutical arts. In preferred embodiments, the formulations are sterilized prior to use.
The ophthalmic formulations described herein are administered to the eyes of a subject, preferably an animal such as a dog, cat, bird, reptile or amphibian, more preferably a mammal, most preferably a human, by any route and through any means where delivery of the histamine content of the formulation to the site of ocular irritation can be achieved. For example, the formulations are administered by spray, by ophthalmic gel, by eye drop, by injection within the eye, or by other methods of administration well known to those of skill in the relevant art. In one embodiment of the present invention, daily dosages in human therapy of the present ophthalmic formulations are of about 1-2 drops per eye, administered about 1-8 times a day (for instance by means of a standard pharmacopeial medicinal dropper of 3 mm in external diameter, which when held vertically delivers 20 drops of water of total weight of 0.9-1-1 grams at 25xc2x0 C.)
The formulations described herein can be used to reduce ophthalmia or eye inflammation resulting from contact lens wear, or conditions such as uveitis, iritis, allergic reactions such as severe hay fever, watery eyes, conjunctivitis such as ocular bacterial infections and ocular viral infections. Various forms of conjunctivitis include: gonococcal conjunctivitis, a form of conjunctivitis caused by the bacterium Neisseria gonorrhea, Inclusion Conjunctivitis, a form of conjunctivitis caused by the bacterium Chlamydia trachomatis, vernal keratoconjunctivitis, keratoconjunctivitis sicca, episcleritis, scleritis, and the like.
Conjunctivitis or inflammation of the conjunctiva can be caused by a number of factors including an allergic reaction to dust, mold, animal dander, pollen, or other allergens, and can be irritated by wind, dust, smoke, and other types of air pollution. The conjunctiva may also be irritated by a common cold or a bout of measles. The ultraviolet light of an electric welding arc, sunlamp, or even bright sunlight reflected by snow or water can irritate the conjunctiva. Conjunctivitis can also be caused by problems with the tear ducts, sensitivity to chemicals, exposure to irritants, and infection by particular bacteriaxe2x80x94typically chlamydia. Conjunctivitis can last for months or years.
When irritated, the conjunctiva becomes bloodshot, and a discharge often appears in the eye. In bacterial conjunctivitis, the discharge may be thick and white or creamy. In viral or allergic conjunctivitis, the discharge is usually clear. The eyelid may swell and itch intensely, especially in allergic conjunctivitis.
Usually conjunctivitis is easy to recognize because it commonly occurs with a cold or allergies. Sometimes, however, conjunctivitis resembles iritis, a more severe eye inflammation, or even acute glaucomaxe2x80x94serious conditions that can lead to a loss of vision. A doctor can usually distinguish the diseases. With the more serious eye conditions, the blood vessels closest to the colored part of the eye (iris) are very inflamed. Although conjunctivitis may cause a burning sensation, it is usually less painful than the more serious conditions. Conjunctivitis almost never affects vision unless the discharge temporarily covers the cornea.
The formulations described herein can also be used to reduce ocular irritation caused by a variety of ocular surgical techniques including LASIK, PK, PRK, and cataract surgery.